Tag Archives: Eosinophilic esophagitis

“If all you have is a hammer…”

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In my training, one of my mentors would be critical of the mentality “scope first, think second.”  He was concerned that too many gastroenterologists/pediatric gastroenterologists used endoscopy as a tool simply “because if all you have is a hammer, the world looks like a nail.”

A recent publication (Clin Gastroenterol Hepatol 2014; 12: 963-69) on first glance, however, provides ammunition to the “scope first” gastroenterologists and undermines the concept that “functional” GI disorders vastly outnumber “organic” GI disorders.  The key finding was that esophagogastroduodenoscopy (EGD) provided an “accurate” diagnosis in 38%.  This included reflux esophagitis in 21%, eosinophilic esophagitis (EoE) in 5%, eosinophilic gastroenteritis (EGE) in 4%, H pylori in 2%, celiac disease 0.6%, and Crohn’s disease 0.4%. This finding is dramatically higher than previous studies.  In fact, in a recent published study (Understanding Idiopathic Nausea | gutsandgrowth) on idiopathic nausea, a control group of patients with chronic abdominal pain had a normal endoscopy in 100%!

In this prospective study of 290 children (ages 4-18 years with a mean age of 11.9 years), the primary indication for upper endoscopy was chronic abdominal pain.  Of this 290, 216 had at least 1 alarm feature and 125 had at least 2 alarm features.  Alarm features were considered to be the following:

  • Nighttime awakening 33.3%
  • Weight loss 15.6%
  • Family history of IBD 8.4%
  • Vomiting 7.8%
  • Dysphagia 6.9%
  • Nocturnal diarrhea 6.7%
  • Gastrointestinal bleed 5.8%
  • Chronic diarrhea 5.8%
  • Unexplained fever 4.4%
  • Arthralgia 4.0%
  • Growth failure 2.4%
  • Perirectal disease 0.7%
  • Delayed puberty 0.2%

There is little debate that abdominal pain in combination with true alarm symptoms (True red flags in recurrent abdominal pain | gutsandgrowth) merits further evaluation.  The aspect of this report that is worthy of close inspection is the diagnostic yield in the 74 patients without alarm symptoms.  The authors note that 25 (33.7%) had a diagnosis established with EGD including 16 with reflux esophagitis, 4 with EGE, 2 with EoE, 1 with erosive esophagitis, 1 with celiac and 1 with H pylori.  The diagnostic criteria for EGE included ≥10 eosinophils per hpf in the stomach and ≥20 eosinophils per hpf in the duodenum.

The authors note that the diagnostic yield was based on gross endoscopic findings in procedure notes or histologic changes in biopsy reports; “final pathology report on biopsies provided the data source for histologic diagnosis.”

In my opinion there are multiple flaws of this prospective study.

1. There is a very high rate of reflux esophagitis in both the alarm group and the non-alarm group patients with chronic abdominal pain.  Of the entire cohort (n=290), the authors identified reflux esophagitis in 21% and this was “primarily histologic esophagitis.”  Furthermore, the authors state that “the presence or response to PPI therapy was not predictive of esophagitis or GERD.”  So, the obvious problems:

  • Presence of histologic reflux esophagitis varies widely based on the interpreting pathologist.  In a prospective study, more than one pathologist interpreting the histology would be useful.
  • Presence of histologic reflux esophagitis does not exclude the likelihood of coexisting functional disorders (related blog post: Why didn’t patient with documented reflux get better with PPI …).  As a practical matter, “slight” or “focal” esophagitis on histology has questionable real-world relevance in pediatric gastroenterology.
  • The authors acknowledge, “current expert consensus indicates that histology has limited value in evaluating pediatric GERD.”  Yet this diagnostic finding is one of the reasons why the authors claim that EGD is so valuable.

2. In the entire cohort, the authors try to validate their findings by indicating that identification of a diagnosis led to medical therapy that was “effective in approximately 67%” of children with short-term followup. (Only 81% had short-term followup outcomes available).  Yet, there is no control group.  How many children with chronic abdominal pain will improve for a short period without an EGD-based diagnosis?  The answer: a lot of them.

3. Limitations include selection bias toward those with more severe symptoms or alarm symptoms.  In addition, this study included only a small number who were considered to have no alarm symptoms.  Finally, the short-term followup makes conclusions about the response to therapy questionable.

This study will be a useful reference for any pediatric gastroenterologist who wants to justify the need for an endoscopy.  The authors note “the majority of children in our study (93%) met criteria for functional gastrointestinal disorders, and a significant proportion (38%) still had significant histologic findings.  Therefore, we conclude the Rome III criteria alone are not sufficient to identify children who require upper endoscopy, and screening for alarm symptoms has limited utility.”

In my opinion, the reliance on histology as well as selection bias weaken the findings of this study.  If a patient with a histologic diagnosis of reflux (or several other entities) and a presentation of chronic abdominal pain does not improve, the pediatric gastroenterologist should remember that only “a poor carpenter blames his tools.”

Bottomline: EGD remains an important tool in evaluating abdominal pain.  However, I think this study substantially overestimates its utility.

Related blog posts:

 

 

 

 

The Latest on EoE and PPI-REE

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A recent study shows similar clinical, endoscopic and histologic findings between eosinophilic esophagitis (EoE) and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) (Aliment Pharmacol There 2014; 39: 603-08 -thanks to Seth Marcus for this reference).

The authors used two databases: one from Walter Reed and one from the Swiss EoE database.  All of these patients were >/=18 years.  Response to PPI was defined as achieving less than 15 eos/hpf and a 50% decrease from baseline following at least 6-weeks of PPI treatment.

Demographics: 63 EoE patients, 40 PPI-REE, mean age 40 years (75% male, 89% Caucasian).

Findings:

  • Similar dysphagia 97% vs. 100% (in EoE and  of PPI-REE cohorts)
  • Similar food impaction 43% vs. 35% (in EoE and  of PPI-REE cohorts)
  • Similar heartburn 33% vs. 32% (in EoE and  of PPI-REE cohorts)
  • Similar duration of symptoms: 6.0 years vs 5.8 years (in EoE and  of PPI-REE cohorts)
  • Similar endoscopic findings too: rings 68% in both groups, furrows 70% in both groups, strictures 49% vs 30% (in EoE and  of PPI-REE cohorts)
  • Similar histology: proximal esophagus 39 vs 38 eos/hpf and distal esophagus 50 vs 43 eos/hpf

Take-home message: EoE and PPI-REE are very similar in presentation and indistinguishable without a PPI trial.

Related blog posts:

 

 

How Common is Eosinophilic Esophagitis?

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There have been numerous epidemiologic studies regarding eosinophilic esophagitis.  A recent summary of a recent study (Clin Gastroenterol Hepatol 2014; 12: 589-96) has been posted on the AGA Journals Blog.  Here’s the link to the full summary:  EoE Prevalence AGA Journal Blog

Here’s an excerpt:

Eosinophilic esophagitis (EoE), which was barely recognized 20 years ago, affects at least 150,000 people in the United States, with three-quarters being adults, report Evan Dellon et al. in the April issue of Clinical Gastroenterology and Hepatology.

EoE, also known as allergic esophagitis, is an allergic inflammatory disease characterized by increased numbers eosinophils in the esophagus. Symptoms include difficulty swallowing, food impaction, and heartburn…

They found that despite its relatively recent description, EoE is frequently diagnosed in the US, with an estimated prevalence of 56.7/100,000 persons. The mean age of patients, surprisingly, was 33.5 years; 65% were male, 55.8% had dysphagia, and 52.8% had at least 1 other allergic condition. Prevalence peaked in men 35–39 years old (see figure).

EoE Prevalence by Age

Dellon et al. identified patients based on the International Classification of Diseases (ICD), 9th revision code for EoE (530.13). They state that this prevalence could be an underestimate, because knowledge of the code and recognition of EoE are increasing…

Take home point: This study shows that EoE in adults and in children is much more common in males than females, especially in those with other allergic diseases.  Given the frequency of those with mild symptoms, the prevalence data are likely to be huge underestimates.

Related blog posts:

 

Eosinophilic Esophagitis and Psychosocial Dysfunction

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There are many medical challenges in treating patients with eosinophilic esophagitis (EoE) and this has been discussed extensively in this blog (some links below).  What is striking in managing these patients and families is how often there are significant psychosocial problems.  Does this disorder serve as an excuse for other issues? Does the altered diet create enormous stress and isolation? Is the diagnosis of EoE an epiphenomenon for many of these patients?

While these questions are not answered, a recent retrospective study from a tertiary care center does provide some data on the frequency of psychosocial dysfunction in children and adolescents with EoE (JPGN 2013; 57: 500-05).

Psychosocial evaluation was offered as part of these patients’ clinical evaluation; this took place in 64 of 152 patients during the study timeframe.  Subsequently, a retrospective review of these patients, who had been offered a 1-hour behavioral health assessment by either a psychologist or social worker, were analyzed.

Key findings:

  • 69% had some psychosocial impairment
  • 64% had social difficulties
  • 41% had anxiety
  • 33% had sleep difficulties
  • 28% had depression
  • 26% had school problems
  • 44% had adjustment problems; this was more common in older children and in children with gastrostomy tubes

The main limitations of this study are its retrospective nature and the fact that only a minority of patients were analyzed; the latter indicates a high likelihood of a selection bias. The severity of EoE was not correlated with these problems, but could have been higher  at a tertiary center.

Take-home message: As with other chronic diseases, EoE patients have frequent psychosocial health problems –this study starts to define the extent of the problem.

Looking behind and looking forward in EoE (part 2)

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While yesterday’s article was good, today’s is really forward-thinking (Gastroenterol 213; 145: 1289-99).  Last year in this blog, I reviewed the use of microRNA for studying EoE (MicroRNA signature for eosinophilic esophagitis | gutsandgrowth), this study expands on this idea with the development of the EoE diagnostic panel (EDP) which is a 96-gene quantitative polymerase chain reaction assay.

The authors (one of whom [JG] has joined our group) used this assay initially in 15 pediatric with EoE, in 14 pediatric non-EoE, and then in a subsequent cohort of 194 pediatric and adult patient samples (fresh or formalin-fixed tissue from one esophageal biopsy).  Of the latter cohort, 91 had histologically-active EoE, 57 had either non-EoE or EoE in remission, 34 were histologically-ambiguous, and 12 had reflux.

Results -first of all you have to see the results to get the best sense of how impressive they are.  Numerous figures show the EDP depictions of patients’ EoE transcriptome patterns.

  • EDP had approximately 96% sensitivity and 98% specificity; EDP’s utility could be underestimated due to limitations in the current ‘gold standard’ for diagnosis
  • EDP can distinguish EoE in remission from healthy controls as well as identify patients exposed to swallowed glucocorticoids.  Thus, with current patients in remission, the tissue may appear healthy; nevertheless, EDP identifies molecular changes in this tissue.
  • EDP can distinguish EoE from reflux

What this study means:

  1. Currently both the diagnostic standards (eg. cutoff values for eosinophils) and remission standards remain questionable.  This molecular test has the potential to raise the standard for both diagnosis and response to treatment.
  2. EDP may elucidate differences in EoE pathogenesis which could vary from patient to patient.
  3. EDP may help in prospective trials and help in clinical practice by identifying patients who are most likely to benefit from the treatments that are available.
  4. EDP may help overcome the patchy nature of eosinophil distribution.
  5. EDP serves as a model for how molecular testing could influence many inflammatory conditions including asthma, inflammatory bowel disease and biliary atresia.

While I think this study is going to be highly influential, I have one unanswered question:  how much will it cost?  In the conclusion, the authors state “the EDP offers an accurate, rapid, informative, and low-cost diagnosis.”  Yet, the authors do not elaborate on the expense of this technology.

Related blog entries:

PPIs -another reference for EoE

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“The outcome of patients with oesophageal eosinophilic infiltration after an eight-week trial of a proton pump inhibitor”

  1. G. Vazquez-Elizondo1,
  2. S. Ngamruengphong1,
  3. M. Khrisna2,
  4. K. R. DeVault1,
  5. N. J. Talley1,
  6. S. R. Achem1,*

Article first published online: 5 OCT 2013

DOI: 10.1111/apt.12513

Link to article: bit.ly/18bA3SS (from John Pohl’s twitter feed)

Methods: Sixty consecutive symptomatic patients with documented oesophageal eosinophilia received open-label omeprazole 20 mg orally twice daily before meals for 8 weeks.  Mean age 48.7 years (18-79).

Results: Clinical improvement occurred in 43 (71.6%), endoscopic signs were reduced in 34 (61.8%) and normalised in 12 (21.8%), and histologically, 34 (56.6%) improved, while 15 (25%) obtained complete resolution. Overall, 22 patients (36.7%) obtained both complete clinical and histological remission

Additional related blog entries:

Nexium versus Fluticasone for EoE

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As noted in previous blog posts (EoE: Drugs, Diets, Dilatation and PPI-REE | gutsandgrowth, EoE –Journal Club (Part 1) | gutsandgrowth, and EoE –Journal Club (Part 2) | gutsandgrowth), proton pump inhibitors are recommended as 1st line therapy in suspected eosinophilic esophagitis (EoE) for several reasons.  Besides the potential for gastroesophageal reflux to cause esophageal eosinophilia, there has been recognition of PPI-responsive eosinophilic esophagitis (PPI-REE).  In adults, the response to proton pump inhibitors, both clinically and histologically, is likely higher than in children; nevertheless, in children it is anticipated that 20-40% of patients with suspected EoE will have a histological remission with PPI therapy.

A recent study in adults suggests that PPIs may in fact outperform topical steroids (Am J Gastroenterol 2013; 108: 366-72).  Thanks to Ben Gold and Seth Marcus for identifying this reference.  This study enrolled 42 patients: 90% male, 81% white, mean age 38 years. It was a prospective single-blinded, randomized controlled trial with newly suspected EoE; half of the patients received esomeprazole 40 mg daily and half fluticasone swallowed aerosol 440 mcg twice a day.  After 8 weeks, all patients had repeat endoscopy; a total of eight biopsies were obtained –four at two locations: 15 cm above LES and 3 cm above LES.  In addition, at the start of the study, patients also underwent 24-h pH/impedance monitoring.  4 of the 21 patients in each group had abnormal degrees of gastroesophageal reflux/gastroesophageal reflux disease (GERD).

Study characteristics note that 62% of patients had coexisting atopic disorders.

Results:

  • There was no significant difference in esophageal eosinophilia response with 19% of the fluticasone and 33% of the esomeprazole achieving an eosinophil count < 5/hpf (P=0.484)
  • In patients with coexisting GERD, all 4 esomeprazole patients achieved histologic remission  compared with none of the fluticasone-treated patients.
  • When the GERD patients were excluded, the histological remission was quite similar: 24% with fluticasone and 18% for esomeprazole.

Overall, this study population had a lower rate of response to topical steroids than in multiple previous studies.  More typically, response rates of ~50% have been reported; however, studies have shown lower responses in some adult studies.  Variability in response could be related to multiple factors included dosage, duration, delivery, and definition of response.  In addition, population characteristics included disease duration and frequency of underlying atopic disease and GERD play a role.

Take-home points: Although this is a small study, it reinforces the fact that PPIs induce a histological response and clinical response in some patients suspected of having EoE regardless of whether GERD is present.  PPIs are considered 1st line therapy.  Topical fluticasone had a lower response rate in this study.  However, in clinical pediatric practice, topical steroids are effective in about 50% of patients.

Additional related blog entries:

Natural History of EoE -Journal Club (Part 3)

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This posting reviews the final article for our eosinophilic esophagitis (EoE) journal club: Aliment Pharmacol Ther 2013; 37: 114-21.

Design: Cross-sectional study of adult EoE patients (≥ 18 years) who were diagnosed at the Children’s Hospital of Philadelphia.  Patients underwent dysphagia questionnaire, Mayo Dysphagia Questionnaire (MDQ-30), and a patient assessment of upper gastrointestinal disorders quality of life questionnaire (PAGI-QOL). Of 140 eligible patients, 53 completed the questionnaires, 66 were unable to be contacted, and 21 refused to participate.

The MDQ-30 has been validated as a tool for esophageal strictures of 15 mm or smaller.  It has not been confirmed as a EoE dysphagia tool.

Diagnosis: According to the authors, a diagnosis of EoE required a >20 eosinohils/hpf after a 2-month therapeutic trial of proton pump inhibitors.

Results:

  • Mean age 20.5 years.  98% were caucasian and 75% were male.  15% had a history of esophageal dilatation.
  • 6/53 had positive dysphagia scores.  However, 18/47 with negative scores reported ongoing difficulty swallowing.
  • 26 (49.1%) of subjects were receiving proton pump inhibitor therapy and 40 (76%) were following allergy-directed dietary elimination.  Most common allergy in this cohort was dairy (49%) followed by peanuts/tree nuts (23%), eggs (9%), wheat (9%), soy (8%), and seafood (2%).**
  • Overall, dietary QOL scores, but not overall QOL scores, were adversely affected by ongoing EoE.

**With regard to dietary therapy, there is a significant discrepancy in reported allergy avoidance in this cohort compared with some previous data published by this center. For example, Liacouras et al (Clin Gastro Hepatol 2006; 3: 1198) reported a  98% improvement with diet treatment (n=351) (2/3rds were treated with elemental diet, mostly NG, with food reintroduction).  Their protocol included rebiopsy after introduction of last new food.  75/242 responded to elimination of specific foods.  Overall pattern of food avoidance after biopsy: milk 45%, eggs 45%, soy 38%, corn 38%, wheat 30%, beef 30%, chicken 20%, potato /oats/peanuts 15%, turkey/barley 11%, pork 8%, rice 5%, green beans 3%, apples /pineapple 1%.*  The reported allergens in this study match up much more closely to a highly-selected group of patients that was more recently reported from their database and is reviewed separately (Picking the right diet for EoE | gutsandgrowth).  In this group, the authors stated that the most common foods by biopsy were the following: milk (35%), egg (13%), wheat (12%), soy (9%), corn (6%).

Study limitations:

  1. Small number of patients
  2. Low response rate/responder bias
  3. Retrospective cross-sectional study -does not provide longitudinal data
  4. Young age of subjects
  5. MDQ-30 not validated for dysphagia in EoE
  6. Tertiary children’s hospital with research focus on EoE
  7. No recent endoscopies in research cohort

Take-home message: EoE is a chronic disease with “little resolution of either symptoms or oesophageal eosinophilia without ongoing treatment.”

 

EoE -Journal Club (Part 2)

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The third article for our journal club: Aliment Pharmacol Ther 2013; 37: 1157-64.

This study involved a literature search which identified 10 articles which described the impact of proton pump inhibitor therapy for suspected eosinophilic esophagitis.  In total, these articles describe 258 patients (152 children and 106 adults).  Five of the studies were retrospective series.  The others included two randomized controlled trials, one randomized noncontrolled trial, and two prospective series.

Results: after PPI treatment, a clinical response was noted in 69% overall and histologic remission was evident in a mean of 44%.  Histologic remission was lower in children (23%-40%).  In two adult studies, both randomized controlled trials, PPI therapy (esomeprazole 40 mg/day) outperformed topical steroids (fluticasone 440 mcg bid); histologic remission was seen in 33% with PPI in both trials compared with 15% and 19% with fluticasone.

Key points in discussion:

  • PPI trial “is mandatory not only to confirm the presence of EoE, but to evaluate for PPI responsiveness.”  Yet, in surveys, …”only one-third of physicians thought it is necessary to initiate a PPI trial before diagnosing EoE.”
  • No clinical, endoscopic, histologic features nor pH testing “have demonstrated capacity to predict response to PPI therapy.”
  • PPI-REE “occurs in at least one-third of patients with suspected EoE, with response rates lower in children.”  Adults may have a higher response due to coexisting gastroesophageal reflux disease.

Related blog entry: gutsandgrowth | Pediatric Gastroenterology